Process for the purifying of iopamidol

ABSTRACT

A process for purifying Iopamidol which uses a butanol as solvent is described. Iopamidol is obtained with high yields, also starting from aqueous solutions of the same and has characteristics in accordance with those required by pharmacopoeia.

This application is a continuation of Ser. No. 08/846,166, filed, Apr.28, 1997, now abandoned. This application which is a continuation ofSer. No. 08/655,671, filed, May 30, 1996, now abandoned, which is acontinuation of Ser. No. 08/281,985, filed, Jul. 29, 1994, now U.S. Pat.No. 5,571,941.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for purifying Iopamidol and,more particularly, to a process for purifying Iopamidol using butanol assolvent.

2. Discussion of the Background

Iopamidol is the International non-proprietary Name (INN) forL-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acidbis-(1,3-dihydroxyisopropylamide). This compound was first described bythe Swiss company Savac A. G. in the British patent no. 1,472,050.Iopamidol is used in diagnostics as non-ionic contrast medium.

Iopamidol is a white high-melting solid. Conventional syntheses ofIopamidol involve a final purification of the product in an aqueoussolution. Thereafter, in order to obtain the product in solid form, itis necessary to crystallize it.

British patent No. 1,472,050 describes that Iopamidol can be isolated byevaporation of the aqueous solution followed by crystallization of thecrude product obtained from ethanol. WO 88/09328 to Bracco IndustriaChimica S.p.A. describes that crude Iopamidol can be obtained byevaporation of the aqueous solution followed by crystallization of thecrude product from absolute ethanol. “Analytical Profiles of DrugSubstances”, vol. 17, pages 115-154, Academic Press, San Diego, 1988)describes that Iopamidol can be crystallized from water, with very slowkinetics, yielding a monohydrate or pentahydrate crystalline product.

Unfortunately when Iopamidol is crystallized from water or ethanol asdescribed in the literature, a crystalline form having the requiredpharmaceutical properties as described in US Pharmacopoeia XXII, page712, cannot be obtained. The product crystallized from ethanol containsan amount of ethanol corresponding to 4000-8000 ppm which cannot beremoved either by heating at high temperatures or under vacuum. Thisproduct is not suitable as a pharmaceutical because its ethanol contentis too high (the USA Pharmacopoeia requires that no impurity can exceed5000 ppm). Similarly, Iopamidol crystallized from water is not suitablebecause in order to remove the water of crystallization, very longheating times at temperatures higher than 100° C. are required.Furthermore, the yield of the crystallization from water is very poorand therefore the process is not suitable from an industrial point ofview.

The literature data regarding the solubility of Iopamidol conflict witheach other and therefore they do not suggest other practical solutionsto solve these problems. For example, British patent no. 1,472,050reports that Iopamidol dissolves very easily in water, has a practicallyunlimited solubility in methanol and has solubility in ethanol of about10% at room temperature. However, one of the inventors of that patent,in a subsequent paper published on Boll. Chim. Farm., 120, 639, (1981),reports that Iopamidol is very soluble in water but is only slightlysoluble in methanol and practically insoluble in ethanol, diethylether,benzene and chloroform. Accordingly, it is desirable to find a practicaland efficient method for purifying Iopamidol.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide amethod for purifying Iopamidol from a crude solid form of Iopamidol.

It is a second object of the present invention to provide a process forpurifying Iopamidol from an aqueous solution of Iopamidol.

It is a third object of the present invention to provide essentiallypure Iopamidol.

The present inventors have now surprisingly found that these and otherobjects can be achieved by crystallizing Iopamidol from n-butanol,sec-butanol, isobutanol or t-butanol. The present inventors have furtherfound that it is not necessary to start from solid crude Iopamidol butit is possible to obtain the desired product by directly treating anaqueous solution of Iopamidol with n-butanol, sec-butanol, isobutanol ort-butanol.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The terms n-butanol, sec-butanol, isobutanol and t-butanol are thecommon names used to indicate the four isomers of butanol having theformula C₄H₁₀O; more precisely, n-butanol is the common name for1-hydroxybutane, sec-butanol is the common name for 2-hydroxybutane,isobutanol is the common name for 1-hydroxy-2-methylpropane andt.butanol is the common name for 1,1-dimethyl-1-hydroxyethane.Hereinafter, for the sake of simplicity, the term butanol is used toindicate indifferently n-butanol, sec-butanol, isobutanol or t-butanol,if not otherwise specified.

Iopamidol can be synthesized using known techniques such as thosedescribed in U.S. Pat. No. 4,001,323; incorporated herein by reference.Crude Iopamidol can be isolated as described in British patent no.1,427,050; WO 88/09328 and “Analytical Profiles of Drug Substances, vol.17, pages 115-154, Academic Press, San Diego; each of which isincorporated herein by reference. Preferably, Iopamidol is isolated bydistillation until crude Iopamidol begins to crystallize.

Thereafter pharmaceutically pure Iopamidol is isolated by crystallizingcrude Iopamidol from butanol. In a first embodiment solid crudeIopamidol is crystallized from butanol. In a second embodiment, anaqueous solution of crude Iopamidol is crystallized by adding butanol toform a crystallization mixture. The amount of residual water in thecrystallization mixture, for example even an amount of water equal tothe weight of Iopamidol, does not effect either the quality or the yieldof pure Iopamidol.

The amount of butanol to be used is from 3 to 20 times (volume/weight)with respect to the amount of Iopamidol which is present in the aqueoussolution. Preferably, the amount of butanol is from 3 to 12 times(volume/weight) with respect to the amount of Iopamidol. Still morepreferably, the amount of butanol is from 3 to 10 times (volume/weight)with respect to the amount of Iopamidol. It is self-evident that whenthere is an azeotropic mixture, butanol can be recovered bydistillization and recycled.

In a third embodiment of the present invention, a third solvent can alsobe added to the crystallization mixture of water, Iopamidol and butanol.The third solvent suitably is able to form a ternary azeotrope withwater. A preferred third solvent is toluene.

From a practical point of view, the direct use of an aqueous solution ofIopamidol is preferred because it is practically and economically moreadvantageous not to remove all the water and because the resultantproduct has a very low content of residual solvent. It is particularlyadvantageous from an industrial point of view to purify Iopamidol froman aqueous solution of Iopamidol and butanol in an amount from 3 to 20times (volume/weight) with respect to that of Iopamidol. The reactionmixture is heated at the boiling temperature to azeotropically removepart of the water. Precipitation of Iopamidol is observed. Thedistillation is continued until the water is reduced to an weight amountequal to or lower than that of Iopamidol. Then, the heating is stoppedand the temperature is brought to 10-30° C., preferably to about 25° C.,and Iopamidol is separated by filtration.

Alternatively, the crystallization mixture of water, Iopamidol andbutanol is added with a third solvent able to from an azeotrope withwater, for example toluene. As above, during the distillation step aprecipitate of Iopamidol begins to form.

Iopamidol obtained by the process of the present invention ispharmaceutically acceptable since the amount of butanol remaining in theproduct is decidedly lower than the required limits. As used herein,pure Iopamidol contains an amount of residual solvent which is less thanthe amount of residual solvent in the crude Iopamidol used as thestarting material. Preferably, the pure Iopamidol obtained has at most2000 ppm of residual solvent. In fact, when Iopamidol is obtaineddirectly from the aqueous solution, the residual solvent is even equalto or lower than 200 ppm. The resultant product has a very highchromatographic purity, higher than hat of the starting product inaqueous phase. Thus, the Iopamidol obtained by the purification processof the invention is particularly suitable for the preparation ofnon-ionic contrast media according to usual techniques.

Furthermore, the crystallization yields are very high, at least higherthan 80% and in most cases also higher than 95%.

As far as the instant process is concerned, mixtures of butanols appearto behave in substantially the same way as the single components andthus mixture of butanols do not depart from the spirit of thisinvention.

Having generally described this invention, a further understanding canbe obtained by reference to certain specific examples which are providedherein for purposes of illustration only and are not intended to belimiting unless otherwise specified.

EXAMPLES

The water content in the azeotrope and in the final product wasdetermined by Karl-Fisher method, while the content of butanol in thefinal product was determined by gas-chromatographic route.

Example 1

Sec-butanol (1600 ml) was added under stirring and by keeping thetemperature at 85° C. to a solution of Iopamidol (200 g; 0.257 moles) inwater (200 ml). The solution was heated to the reflux temperature, whiledistilling at ordinary pressure the mixture sec-butanol/water at therate of 10 ml/minute. During the distillation Iopamidol begins toprecipitate. In all, 853 g of sec-butanol/water mixture (water=23.1%)were distilled off. The suspension was cooled to 25° C. in 1 hour, keptat 25° C. for one further hour and the precipitate was filtered off andwashed with sec-butanol (2×100 ml). After drying under vacuum at 60° C.until constant weight, Iopamidol (192 g; 0.247 moles; 96% yield) wasobtained; water content=0.15% and residual solvent sec-butanol 200 ppm.

Example 2

Sec-butanol (1800 ml) was added under stirring and by keeping thetemperature at 80° C.±2° C. to a solution of Iopamidol (200 g; 0.257moles) in water (270 ml). The solution was heated to the refluxtemperature, while distilling at ordinary pressure the mixturesec.butanol/water at the rate of 10 ml/minute. During the distillationIopamidol begins to precipitate. In all, 700 g of sec-butanol/watermixture (water=22%) were distilled off. About 116 g of water were stillpresent. The suspension was cooled to 25° C. in 1 hour, kept at 25° C.for one further hour and the precipitate was filtered off and washedwith sec-butanol (2×100 ml). After drying under vacuum at 60° C. untilconstant weight, Iopamidol (190 g; 0.244 moles; 95% yield) was obtained;water content=0.2%, residual solvent sec-butanol 180 ppm.

Example 3

Sec-butanol (150 ml) and toluene (20 ml) were added under stirring andby keeping the temperature at 80-85° C. to a solution of Iopamidol (20g; 0.0257 moles) in water (30 ml). The mixture was brought to reflux anda part of water was azeotropically removed. During the distillationIopamidol begins to precipitate. In all, 12 ml of water were distilledoff. The suspension was cooled in 1 hour to 25° C., kept at 25° C. forone further hour and the precipitate was filtered off and washed withsec-butanol (2×10 ml). After drying under vacuum at 60° C. untilconstant weight, Iopamidol 19.2 g; 0.0247 moles; 96% yield) wasobtained; water content=0.2%, residual solvent sec-butanol 100 ppm andtoluene 2 ppm.

Example 4

N-butanol (200 ml) was added under stirring and by keeping thetemperature at 80° C.±2° C. to a solution of Iopamidol (20 g; 0.0257moles) in water (20 ml). The solution was heated to the refluxtemperature, while distilling water (8.5 g) with a florentine flask.During the distillation Iopamidol begins to precipitate. Thedistillation was completed by further distilling 54 g of n-butanol/watermixture (water=21%). The suspension was cooled to 25° C. and theprecipitate was filtered off and washed with n-butanol (2×10 ml). Afterdrying under vacuum at 60° C. until constant weight, Iopamidol 19.4 g;0.025 moles; 97% yield) was obtained; water content=0.2%, residualsolvent n-butanol 70 ppm.

Example 5

N-butanol (200 ml) was added under stirring and by keeping thetemperature at 80° C.±2° C. to a solution of Iopamidol (20 g; 0.0257moles) in water (80 ml). The solution was heated to boiling, whiledistilling water (72 g) with a florentine flask. During the distillationIopamidol begins to precipitate. The distillation was completed byfurther distilling 50 g of n-butanol/water mixture (water=21%). Thesuspension was cooled to 25° C. and the precipitate was filtered off andwashed with n-butanol (2×10 ml). After drying under vacuum at 60° C.until constant weight, Iopamidol (19.3 g; 0.0248 moles; 96.5% yield) wasobtained; water content=0.2%, residual solvent n-butanol 80 ppm.

Example 6

A solution of Iopamidol (20 g; 0.0257 moles) in water (20 ml) wasbrought to residue under vacuum (70° C.—30 mmHg). Sec-butanol (150 ml)was added to the residue containing water (2.3%) and the heterogeneousmixture, kept under stirring, was brought to reflux and kept at thereflux temperature for 30 minutes. The suspension was cooled to 25° C.and the precipitate was filtered off and washed with sec-butanol (2×10ml). After drying under vacuum at 70° C. until constant weight,Iopamidol (19.4 g; 0.025 moles; 97% yield) was obtained; watercontent=0.2%, residual solvent n-butanol 1300 ppm.

Example 7

A mixture of Iopamidol (20 g; 0.0257 moles), water (20 ml) andisobutanol (150 ml) was heated to reflux while distilling water (9 ml).

During the distillation Iopamidol begins to precipitate. In all, 47 g ofisobutanol/water mixture (water=18.3%) were distilled off. Thesuspension was cooled to 25° C. and the precipitate was filtered off andwashed with isobutanol (2×10 ml).

After drying under vacuum at 60° C. until constant weight, Iopamidol(19.7 g; 0.0254 moles; 98.5% yield) was obtained; water content=0.17%,residual solvent isobutanol 100 ppm.

Example 8

T-butanol (150 ml) was added under stirring and by keeping thetemperature at 70° C. to a solution of Iopamidol (20 g; 0.0257 moles) inwater (20 ml). The suspension was heated to the reflux temperature,while distilling at ordinary pressure 57 g of the mixturet-butanol/water (water=13.3%). During the distillation Iopamidol beginsto precipitate. The suspension was cooled to 25° C. and the precipitatewas filtered off and washed with t-butanol (2×10 ml). After drying undervacuum at 60° C. until constant weight, Iopamidol (16 g; 0.0206 moles;80% yield) was obtained; water content=0.25%, residual solvent t-butanol150 ppm.

Example 9

Charcoal (8 Kg) was added to an aqueous solution (2500 l) containingIopamidol (about 290 Kg). After stirring for 30 minutes and filtrationof the charcoal, the resultant solution was concentrated under vacuum upto a final concentration of 70-75% (w/w). The concentrated solution washeated to 85° C. and, while keeping the temperature between 80° C. and85° C., sec.butanol (1300 Kg) was added. At the end of the addition, theresultant suspension was kept at 80-85° C. for 30 minutes and thencooled to 25° C. After stirring at 25° C. for 2 hours and filtration,the solid residue was washed with sec-butanol (190 Kg) and dried at50-55° C. under vacuum. Pure Iopamidol (275 Kg) was obtained.

Having now fully described the invention, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit or scope of the inventionas set forth herein.

What is claimed as new and desired to be secured by Letters Pantent ofthe United States is:
 1. A process for purifyingL-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acidbis-(1,3-dihydroxyisopropylamide) (Iopamidol) comprising the steps of:dissolving a crude solid of Iopamidol in a solvent selected from thegroup consisting of n-butanol, sec-butanol, isobutanol, t-butanol andmixtures thereof; and crystallizing pure Iopamidol therefrom, whereinsaid pure Iopamidol has less residual solvent than said crude Iopamidol.2. The process of claim 1, wherein the weight of Iopamidol to the volumeof solvent is 3 to
 20. 3. The process of claim 1, wherein said solventis n-butanol.
 4. The process of claim 1, wherein said solvent issec-butanol.
 5. The process of claim 1, wherein said solvent isisobutanol.
 6. The process of claim 1, wherein said solvent ist-butanol.
 7. A process for purifyingL-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acidbis-(1,3-dihydroxyisopropylamide) (Iopamidol) comprising the steps of:treating an aqueous solution of Iopamidol with a solvent selected fromthe group consisting of n-butanol, sec-butanol, isobutanol, t-butanoland mixtures thereof to obtain a mixture containing Iopamidol; andcrystallizing pure Iopamidol therefrom, dissolving a crude solid ofIopamidol in a solvent selected from the group consisting of n-butanol,sec-butanol, isobutanol, t-butanol and mixtures thereof; andcrystallizing pure Iopamidol therefrom, wherein said pure Iopamidol hasless residual solvent than said crude Iopamidol.
 8. The process of claim7, wherein said solvent is n-butanol.
 9. The process of claim 7, whereinsaid solvent is sec-butanol.
 10. The process of claim 7, wherein saidsolvent is isobutanol.
 11. The process of claim 7, wherein said solventis t-butanol.
 12. The process of claim 7, wherein said aqueous solutionof Iopamidol is the product of a synthesis of Iopamidol.
 13. The processof claim 7, wherein said treating step comprises adding said solvent tosaid aqueous solution of Iopamidol to form said mixture containingIopamidol and distilling said mixture to remove partially or completelythe water which is present.
 14. The process of claim 7, which furthercomprises the step of treating said mixture containing Iopamidol with athird solvent to obtain a ternary azetrope.
 15. The process of claim 14,wherein said third solvent is toluene.
 16. PurifiedL-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acidbis-(1,3-dihydroxyisopropylamide) (Iopamidol) prepared by a processcomprising: dissolving a crude solid of Iopamidol in a solvent selectedfrom the group consisting of n-butanol, sec-butanol, isobutanol,t-butanol and mixtures thereof; and crystallizing purified Iopamidoltherefrom, wherein said purified Iopamidol has an amount of residualsolvent less than said crude Iopamidol.
 17. A non-ionic contrast mediumcomprising L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acidbis-(1,3-dihydroxyisopropylamide) (Iopamidol) purified by: dissolving acrude solid of Iopamidol in a solvent selected from the group consistingof n-butanol, sec-butanol, isobutanol, t-butanol and mixtures thereof;and crystallizing purified Iopamidol therefrom, wherein said purifiedIopamidol has an amount of residual solvent less than said crudeIopamidol.
 18. A non-ionic contrast medium comprisingL-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acidbis-(1,3-dihydroxyisopropylamide) (Iopamidol) purified by: treating anaqueous solution of Iopamidol with a solvent selected from the groupconsisting of n-butanol, sec-butanol, isobutanol, t-butanol and mixturesthereof to obtain a mixture containing Iopamidol; and crystallizingpurified Iopamidol therefrom, wherein said purified Iopamidol has anamount of residual solvent less than said crude Iopamidol.
 19. Thepurified Iopamidol of claim 16 which contains less than or equal to2,000 ppm of residual solvent.
 20. The purified Iopamidol of claim 16which contains less than or equal to 1,300 ppm of residual solvent. 21.The non-ionic contrast medium of claim 17, wherein the purifiedIopamidol contains less than or equal to 2,000 ppm of residual solvent.22. The non-ionic contrast medium of claim 17, wherein the purifiedIopamidol contains less than or equal to 1,300 ppm of residual solvent.23. The non-ionic contrast medium of claim 18, wherein the purifiedIopamidol contains less than or equal to 2,000 ppm of residual solvent.24. The non-ionic contrast medium of claim 18, wherein the purifiedIopamidol contains less than or equal to 1,300 ppm of residual solvent.25. The purified Iopamidol of claim 16, wherein the solvent issec-butanol.
 26. The non-ionic contrast medium of claim 17, wherein thesolvent is sec-butanol.
 27. The non-ionic contrast medium of claim 18,wherein the solvent sec-butanol.
 28. The purified Iopamidol of claim 19,wherein the solvent is sec-butanol.
 29. The purified Iopamidol of claim20, wherein the solvent is sec-butanol.
 30. The non-ionic contrastmedium of claim 21, wherein the solvent is sec-butanol.
 31. Thenon-ionic contrast medium of claim 22, wherein the solvent issec-butanol.
 32. The non-ionic contrast medium of claim 23, wherein thesolvent is sec-butanol.
 33. The non-ionic contrast medium of claim 24,wherein the solvent is sec-butanol.